Comparison of anileridine and meperidine as obstetric analgesia

Comparison of anileridine and meperidine as obstetric analgesia A double blind study of 471 patients

DENIS CAVANAGH, M.D.* CLAUDE LECART, M.D. JANET C. CASSADY, M.S. IRIS M. KIEM, M.S., M.P.H. A1iami, Florida

T H E s E A R c H for safer and more satisfactory obstetric analgesia has led to the use of a variety of analgesic agents. In recent yean;, it has become customary to combine these with scopolamine, barbiturates, or phenothiazine derivatives. The aim of all such combinations should be to bring maximum relit?f to the mother without endangering the fetus. Meperidine is the most widely accepted obstetric analgesic agent in use at the present time. Anileridine is a chemically related analgesic agent in vvhich the N-methyl group of meperidine is replaced by N- ( paminophenethyl) and a dihydrochloride is formed. 1 • " The structural formulas are shown in Fig. 1. Studies on the effects of this drug on groups of animals were reported in comparison with meperidine by Orahovats, Lehman, and Chapin. 2 Stage" reported on a clinical trial of anileridine as a primary anesthetic agent. Keats, Telford, and Kurosu,' investigated the analgesic potency of anileridine in postoperative patients and 21 mg. of anileridine

was determined to be the analgesic equivalent of 50 mg. of meperidine. \Vizenberg and his co-workers" reported on the use of anilericline, and anileridine plus a barbiturate in labor for the control of pain in 155 service patients in the Sinai Hospital in Baltimore. They decided after initial studies that the most satisfactory route of administration was intravenous injection. The usual dose was 50 mg. anileridine, with 0.4 or 0.6 mg. of scopolamine in the initial do~e. They reported that most patients went to sleep and stayed asleep for an hour, though the patients were easily aroused. After an hour, supplementation was usually required. Perphenazine is a phenothiazine derivative previously reported to be useful in controlling emesis during labor. G The phenothiazines have antihistaminic activity,'' s in addition to their sedative effect. They reduce the pressor effect of the catecholamin(·s, but do not affect the brain content of serotonin. They are reported to potentiate and prolong the action of sedatives. narcotics and anesthetic drugs, exert a potent antiemetic drect by selective action of the chemoreceptor trigger zone, and interfere with the central heat regulating mechanism.7· 9 The present study was undertak,·n to e\·aluate the effect obtained by anileridine in dosage equivalent to meperidine and to

From the Department of ObstetricsGvnecology and the Department of Medicine, Unic•ersity of Miami School of Medicine, Jackson Memorial Hospital. *Present address: Department of Obstetrics, St. Louis University School of Medicine, St. Louis, Missouri.

213

214 Cavanagh et al.

:O:wpteinht't

\rl!.

19{;0

Obst. & (;vn•·<·

•2HCI

•HCI

Meperidine

J.

Anileridine

Fig. 1. Structural formulas of meperidine and anikridinP.

measure the effect of the addition of perphenazine to each of these drugs. A double blind study was designed to compare the effect on maternal analgesia and sedation of ( 1) meperidine, 75 mg. alone; (2) anileridine, 30 mg. alone; (3) meperidine, 75 mg. and perphenazine (Trilafon) 5 mg.; and ( 4) anileridine, 30 mg. and perphenazine (Trilafon) 5 mg. In addition, all four treatment groups received 0.4 mg. of atropine sulfate and 0.5 mg. of levallorphan tartrate (Lorfan) with each primary injection. Recently, we attempted to evaluate the relative merits of two phenothiazine derivatives, promethazine and propiomazine hydrochloride/0 when administered with 50 mg. of meperidine hydrochloride. This previous study provided some basic data on meperidine potentiation. The main aim of the present study was to compare the effects of this almost universally accepted drug of choice with a comparable analgesic agent in equivalent dosage. Methods and materials

Four hundred and seventy-one patients delivered on the Staff (Ward) Service of the Department of Obstetrics-Gynecology of the University of Miami School of Medicine were evaluated. The study was restricted to those indigent patients whose

pregnancies were essentially uncomplicated; any patient who might require drugs other than those to be administered during the study was excluded. Patients were randomly assigned to one of the four treatment groups. The study was double blind. On each patient's study sheet, information was recorded as to the time of onset and length of labor, drugs given (with amounts i, times of injection, degree of pain relief afforded, cervical dilatation, blood pressure. pulse rate, fetal heart tones, anesthetic used, mode of presentation, and type of delivery. The condition of the infant wa~ rated by thE' Apgar scoring system at I and .) minutes after birth.U The drugs \Vere almost always administered intramuscularly and usually as soon as possible after it had been ascertained that labor was fully established; the patient's response was noted :iO to 45 minutes following this initial dose. For 79 per cent of the patients, only one injection was given. If further sedation \vas required, repeat injections of the "study drug'' or a known analgesic agent were givf~n at 3 to 4 hour intervals, the time and dose of drug injected being recorded. Comparative judgment as to the effect obtained was made as objectively as possible. Four descriptive categories were used as follows: RPsponse A-~no effect, restless, marked reaction to pain. Response B~--awake, re-

Volume 96 :--lumbt·r 2

Obstetric analgesia

!axed, moderate reaction to pain. Response C-asleep, awake with stimuli or contraction, mild reaction to pain. Response D-comatose, no significant response to stimuli or pain. Space was also provided for "other" response to be described. Because of two independent emphatic descriptions of an "other" response completdy different from those described on the form, it was decided to add a fifth response to the tables. This is Response E-stuperous, but no pain relief. Of the 4 71 women included in the study. 209 (44 per cent) were white and 258 (55 per cent) were Negro, with no racial information concerning the remaining one per cent. About three-fourths were multiparas and the remainder were primigravidas. Thirty-one per cent of the white patients were primigravidas compared with 19 per cent of the Negro patients. The age distributions of the patients for the 4 treatment groups were similar. Although most of the patients had received antepartum care, at

215

least 15 per cent had no antepartum care whatever. The patient's psychic state was evaluated on admission. As seen in Table I, 60 p<·r cent of all the patients were "calm" on admission, 40 per cent were "apprehensive." and fewer than 1 per cent were ''hysterical." This table also shows that a slightly greater proportion of the primigravidas were apprr·hensive, in both racial groups. Also, in corresponding parity groups, there was a slightly greater proportion who were apprehensin~ among the white patients. All of thesf.' observed differences were far from statistical significance. As shown in Table II, primary medications were given when dilatation was 3 cr11. or less in 13 per cent, 4 or 5 em. in 51 pt-r cent, and 6 em. or more in 32 per cent. In 4 per cent of cases, dilatation was not n~­ cordcd. Although dilatation was observed to be somewhat greater among those patients who received meperidine than among tho;.e

Table I. Comparison of psychic state of white and Negro patients, on admission, in relation to parity Race

Parit.v

White

Primigravida

34·

53

30

'f7

White

Multipara

81

58.8

56

-10.5

0. 7

138

White

Total group

115

57

86

+2 5

0.5

202

Negro

Primigravida

29

58

21

12

129

6:~

76

:~6.5

0.5

158

62

97

37.6

0.4

256

273

59.6

O..J.

458*

Negro

Multipara

Negro

Total group

Totalr

Total White and

0

0

+O

183

64

0

0

50 206

*All of the ahovc information \vas not available for some patit"'nts and thf'y could not be included hen·.

Table II. Comparison of cervical dilatation of women m four treatment groups when study drug was given

Meperidine Anileridine Meperidine and Anileridine and Totals

9 21

15 16 61

9 16 13 12 5 13

51 64 63 63 241

52 50 54 49 51

38 36

39 28

%

31 3::1

42 152

32

0

7 3

7

17

()

6 2 5.5 4

98 128 117 128

471

216

Cavanagh et al.

St'ptPmhcr l-1. lqhh J. Oh:-t. & { ;ynn'

\w,

\Vho received anileridine, this is not statistically significant (0.5 > P 0.31.

responsP D represented the maximum analeirect. neither it nor n·spome E ''l'i't· cnnsidered desirable. R<';;ponSl' (: was cot1· sidered to be the most favorable t\iw of dTect. The Apgar scores of the infanb hu111 of patients with respons" (: differed to no important extent from thosP born of mntlwr> with n·sponses A and B Table l V · Higher ;:malg·esic dosage would ce~tt•w ;, shift of all responses so lllOn; \\omen would lw in tiw comatose group ..·\ fact worHn· nl

>

Results and comment

No statistically significant difference whatever in the response pattern for the four treatment groups was evident (Table III). From 23 to 28 per cent of each treatment group showed response A.: from 50 to 55 per cent showed response B; and from 17 to 2::1 per cent showed response C. Although

Table III. Comparison of responses in four trcatnwnt ~roups

Meperidine Anileridine Meperidine and Anileridine and Totals

----

------~

27

11

'27

:)2

28

'i:i

20

30

23

5~

29

120

26

)•>

96

:!+6

1-

'I

~0

.,

'I

I)

(I

:l

')

7

L1

1:

!l !I

!>

il

I' II

12H II 7 128

171

·I

~·

Table IV. Distribution of Apgar scores by treatment group and type of n·spome One minute

Meperidine Anileridine Meperidine and pt>rphenazine Anileridine and perphenazine

:>

~1

1

Totals

·)

'!.

0

()

6

Rn pon.,·e A B

2 J.

c:

2+

2·1-'i :.>1

69 9il

70.5*

'!.7

76

t

27

2:1

H6

7:\

:l

\

0

(i

19

n

JOB

fH

97

:20.5

Hll

i7

_,

2

')"'

+7

'I

()

0

D E

0

f)

()

n

0

Totals

6

u

97

19 ·~

2:! 19 20 57

911 i7 :I

n

20 7

*Pt
.,

HO

I I

100

•)

159

-- - - - - - - an· dut• to

()

n

0

0

v.

:~

0.8 -·

Cjj

II~

q;)

1 I

r·

_I

,,

H9

:!.5

ll:i

)

<):2*

120

'I:'J !J.')_")

9!),) (l;)

')

,,

9:1

I"!

()

()

II

·)

11

"

H7

97 Hh ]I )II ~15.1

~-----

-,;nmt'

ca_q~s

recorded.

Table

:I 5

2

ll.5 1

71i.5

--

difrrrf'nn·~

11

IU!

75

90

f.

n

ll

77

1H9

2

•)

ill \\-hich no information

\\,--\•.

Relationship between psvchic state on admission and type of response Uespmue

A

R No.

Calm

Totals

1'\.'i 6'l

19.5 33.5

2

100

120

26

15+

91

TotaL• 5.'i 48.5

0

0

2+5

52

66 30

2-~

I)

0

96

20

5

1.5 l

II

(I

2

I

0

()

0

I)

7

1.5

:.!

11.:)

16

280 188

,,

l71i

Volume 96 ~umbPr

Obstetric analgesia

2

note is that neither of the 2 cases placed in response E received any perphenazine so that the phenothiazine could not be implicated. Both women received 75 mg. meperidine (Table III). As shown in Table V, there was a difference in the response shown by patients according to psychic state at the time of drug administration ( P > .001). Among the apprehensive patients, one in 3 showed no response, whereas among the calm patients, only one in 5 were in the .. no response'' category. Separate tables were prepared showing the treatment responses in calm women (Table VI) as distinct from those in the apprehensive and hysterical categories (Table VII) to ensure that differences in the proportions of each psychic state in the various treatment groups had not biased the results against any particular drug combination. Among women calm on admission, the response patterns for meperidine and anileridine were similar. It is interesting to note that the additional effect of perphenazine, at this dosage of meperidine or anilcridine, did not appear to be beneficial to the calm patients and the "routine"

217

use of such an adjunctive agent is then.fon~ of questionable wisdom. When only those women who were apprehensive or hysterical on admission are considered however. tlw pattern of response to anileridine with pcrphenazine ( 0.10 > P > 0.05) suggested a possible "potentiation" of the analg-esic (Table VIIl. Although the patients receiving meperidirw tended to have shorter time intervals between the administration of the study dru~ and delivery (Table VIII) and shorter total lengths of labor (Table IX), it should also be noted that a higher proportion of th1· women receiving anileridine were in tlw early stages of labor (Table II) and, in addition, a higher proportion of those receivin~ anileridine were primigravidas (Table X'.'. Thus, it is difficult to attribute any "prolongation of labor'' effect to anileridine. Pf'r phenazine had no significant effect upon either interval from study drug to deliven· or the total length of labor ( P > 0.5) . The maternal side effects attributable to the various combinations were minimal. Vomitin~ followed the injection of "stndy drug" in

Table VI. Comparison of responses in four treatment groups when only those women who were calm on admission are considered

Treatment group Meperidine Anileridine Meperidine and perphenazine Anileridine and perphenazine

9 12 17 17

15 17 22 24

Totals

55

19.5

33 39 45 37 154

54 55.5 58.5 51

17 18 15 16

28 26 19.5 22

2 1 0 2

55

66

23.5

5

3 1.5

0 ~

61 70 77 7'J. :280

Table VII. Comparison of responses in four treatment groups when only those women who were apprehensive or hysterical on admission are considered

Meperidine Anileridine Meperidine and perphenazine Anileridine and perphenazine

14

38

18

40

49

3

23 15

25

43

9

Totals

65

13

38 23 34

8 15.5

19 29

49

,'j

52

13

13

23

0 1 0 1

91

48

30

16

2

0 1.5

0 2

2

5

:n

0 0 0

0 0

58 :>9 56

2

1

190

0

218

September- 11. Pthtt

Cavanagh et ol.

\m J.

Table VIII. Time between administration of study drug and delivery for in four treatment groups

Meperidine Anileridine Meperidine and perphenazine Anileridine and

26 20

26

')~

_,

26

20

19

21

20 16.5

R

2t

27

23

3+

29

IR

l'i.S

25

32

Totals

110

16

'-)

:{

9H

31

10

H

I :?8

6

.'J

26

2~.5

\l

!l

II'!

;

Lil

;)

II J

16

20

16

19

15

16

12

:n

29

10+

22

78

17

:n

8

119

25

Table IX. Total length of labor of women in four treatment groups ---- ·-···----·· ·-- ·- ··----------- - - - - - - - - - - - - --------I Treatment group Meperidine Anileridine Meperidine and perphenazine Anileridine and Totals

1-

+ :!.)

-----~---··

-·~---

I

wottlt'll

40

25

-------------- -------

& f}, 1wc

5.S

R

')0

__ ,

Oh~:t.

I 6hours '' 12 -N-0~-%--- .N;--I %-Lw ''"" 6 hours

12 to 24 hours

No.

'.:'~

24 hours

I

and ocer

I

----------------

I

%

No.

No in formatinn

i

No.

r;{J

!Total'

--

31

2+

50

40 '19

22 32

22 21

4 ll

6

h

1:2il

35

30

50

·E-l

21

1B

4

3

ti

117

38

30

47

36

:m

:w

+

:l

136

29

lll6

40

II :1

2+

20

4

16

:)

171

32

39

33

98

4

I:.!B

Table X. Comparison of parity of women m four treatment groups

Meperidine Anileridine Meperidine and perphenazine Anileridine and Totals

24

22.5 20

11 17

11 13

()


-1:7

·12 37

()

26

26

41

33

'}

l·

l.W

26

22

21

18

;)'J

1+

IS

13

'\

:B

25.7

:c!fl

22 6

25

98

21

J 16

24.5

2~

----~~~~----

only 3 patients; one of these women received meperidine and 2 received meperidine and perphenazine. Thus, in contrast to the experience of Phillips and his coworkers,6 we did not find that the addition of perphenazine was helpful in this regard. As an index to over-all evaluation of the infant condition, the Apgar ratings were examined for possible depressant action (Table IV), Comparing the scores of all the infants from mothers receiving anileridine with the scores of the infants from mothers

')I)

39

12

190

40

12

..

·-·-~-----

----

9

f

17

n7

l2il

2

-} 7 I

rece1vmg meperidine, the anilcridine group had higher (0.10 > P > 0.05\ Apgar ratings at 1 minute. \·Vhen the mother recPived meperidine alone, the Apgar scores were 7 or less in 28 per cent as compared with 22 per cent ;vhen anileridine was given. Although this held even whPn the type of anesthesia was considered . the difference was smaller in the 5 minute Apgar ratings (0.2 > P 0.1). Perphenazine apparently bad no depressant action of its own, since, whet1 it was used in conjunction with anilericline. the Apgar scores observed were actuallY

Volume 96 :\ umbi~r 2

higher than in the other three treatment groups with only 15 per cent of the infants having Apgar scores of 7 or less, at 1 minute.

Obstetric analgesia

219

no more comfortable than if either analgesic agent had been used alone. Summary

Conclusions Although many variables may enter into a study of this nature, the possibility of obtaining an incorrect impression is minimized when a sufficient number of patients are included, a strictly random assignment of patients is employed, and evaluation of response is made without knowledge of treatment received. The evaluation criteria were scrutinized closely. Since it is generally accepted that tranquility results in improved tolerance of painful stimuli, we used response categories in which statements regarding the degree of sedation and analgesia were combined. Recently, however, Keats, Telford, and Kurosu 12 have shown that sleep or sedation is not necessarily associated with pain relief. In some instances, the evaluating obstetrician was uncertain as to which cate,gory best described the patient's total response, it being difficult to differentiate between analgesic and sedative effects. When the apprehensive patients were considered, the sedative-analgesic combination of perphenazine and anileridine produced an increase in patient comfort as compared with either narcotic given alone (0.10 > P > 0.05 \ . Although no troublesome side effects were encountered when a phenothiazine dcrivatiYe was used, it appeared that the actual pain relief was distinct from the sedative effect and appeared to be entirely dependent on the analgesic agent. In most cases. however, the patient's reaction during a contraction was thought to provide a useful guide to the analgesic effect obtained. Also, it is interesting that when only calm patients were considered, and the perphenazine added to the analgesic agent, labor was

REFERENCES

I. Weijlard, J., Orahovats, P. D., Sullivan, A. P., Jr., Purdue, G., Heath, F. K., and Pfister, K., III: J. Am. Chern. Soc. 78: 2342, 1956. 2. Orahovats, P. D., Lehman, E. G., and

Anileridine, a relative newcomer to the field of obstetric analgesia, was compared with meperidine in a double blind study involving four treatment groups. These treatment groups were as nearly alike in size and make-up as it is possible to obtain with a random sampling of patients. Four hundred seventy-one women were given a primary injection of either 75 mg. meperidine (Group 1), 30 mg. anileridine (Group 2 i , 75 mg-. meperidine with 5 mg. perphenazinc (Group 3), or 30 mg. anileridinc with 5 mg. perphenazine (Group 4). All four of the treatment groups recf:'ived 0.4 mg. of atropille sulfate and 0.5 mg. levallorphan tartrate. The state of anxiety of each v.:oman was noted on admission and an eYaluation of combined sedative-analgesic efTrct was made following the primary injection of medication. The patient's behavior in the postmedication period was noted, and thr infants were rated by Apgar scores at I and ) minutes after delivery. The analgesics produced almost exactly comparable efTects, with 30 mr;. anileridine apparently bein~ equivalent to 75 mg. meperidine. When a phenothiazine derivative was added to either analgesic, an increase in the optimum response was obtained among the apprehensive patients but not in the calm patient. This increase was not statistically significant. Apgar ratings were essentially the same in all four treatment groups and indicated that anileridine, in equivalent dosage, had no more depressant effect on the fetus than meperidine whether or not these drugs were combined with the phenothiazine derivatiw. No significant side effects were noted following the use of either analgesic agent.

Chapin, E. W.: J. Pharmacol. & Exper. Therap. 119: 26, 1957. 3. Stage, J. T.: J. Florida M. A. 44: 143, 1957. 4. Keats, A. S., Telford, J., and Kurosu, Y.: 18: 690, 1957.

220

Cavanagh et al.

~·wpt~·mh<•r \111.

5. WizPnberg, M . .J.. Siegt>l, I. A., Korman, W., and Rosenthal. H. X: AM. ]. OnsT. & GYNEC. 78: .J.05, 1959. fi. Phillips, 0. C., Lyons, W. B .• Campbell. C .. and Frazier, T. M.: Obst. & Gynec. 15: 182, 1960. 7. Frit>nd, D. G., and Hamlin. J. T.: Drugs of Choice, 1960-1961, St. Louis, 1960, The C. V. Mosby Company, p. 115.

J-

()JJ'>f. Q;

1:·), l'1f)h h\lWI

8. Wortis, S. B.: Postgrad. Med.: 26: fi.J:ti. 1'1 1lJ 9. Goshen, C. E.: G. P. 21: 106. 1960. 10. Powe, C. E., Kiem. I. M .. Fromhagen, { .. and Cavanagh, D.: J. A. M. \. 181: ..'Oll 196'2. l 1. Apgar. V.: New 't'ork J. M<"d.: 55: 2:1ti-, 1955. 1'' Keats. :\. S .. Telford, J .. and Kurom. Y :\ru,sthesiology 22: 3L 19fi I